Macrophage stimuling protein (MSP) is a serum protein originally purified as a protein that made mouse resident peritoneal macrophages capable of responding to the chemoattractant C5a. The receptor for human MSP is the protein Ron and the expression of Ron is found on the cell surface of various types of cells such as macrophages and keratinocytes, suggesting broad MSP activities on different types of cells. We previously cloned a cDNA for human MSP. By Northern blot analysis, we found that MSP mRNA was predominantly expressed in liver. To investigate the mechanisms involved in the liver-specific expression of MSP mRNA, we investigated the mechanisms of the MSP gene transcription and have found that the transcription of the MSP gene is regulated by two cis-elements, a positive regulatory element (PRE) and a negative regulatory element (NRE). The PRE carries a sequence "CCAAT", and a trans-activator, CCAAT-binding transcription factor (CBF) also known as NF-Y, binds to the PRE and activates the transcription of this gene. Since CBF/NF-Y is ubiquitously expressed, the binding of CBF/NF-Y does not account for the liver-specific expression of this gene. The transcription of the MSP gene appears to be negatively regulated in non-hepatic cells by the binding of some repressors to the NRE. Recently, we and others have found that hepatocyte nuclear factor-4 (HNF-4) binds to a sequence in the NRE region. Our hypothesis is that in hepatocytes HNF-4 binds to the HNF-4 binding site located in the NRE region of the gene and inhibits the binding of the repressors to the NRE, resulting in the liver-specific expression of MSP mRNA.